Acute lung injury is an important consequence of sepsis and trauma that continues to carry a high mortality. Acute lung injury often occurs as part of the broader syndrome of multiple organ failure. The mechanisms that initiate and modulate acute lung injury in humans with sepsis need to be better defined in order to design specific therapies that can be used to protect the lungs and systemic organs. The major goal of this proposal is to investigate the cellular and molecular mechanisms that mediate acute lung injury in sepsis. We will test two major hypotheses: 1) that CD14 and a specific lipopolysaccharide binding protein (LBP) in the airspaces mediate and potentiate the inflammatory response in the lungs of patients with acute lung injury; and 2) that strategies designed to interrupt CD14-dependent inflammatory mechanisms will minimize the local and systemic inflammatory consequences of intrapulmonary infections, and protect the host. Our Specific Aims are: 1) to define the roles of CD14 and LBP in lung inflammation in critically ill patients with acute lung injury; 2) to identify the critical interactions that determine the net bioactivity of LPS in the airspaces of patients with lung injury; and 3) to test the effectiveness of neutralizing sCD14 in the airspaces and the systemic circulation of animals with diffuse lung injury arising either from non- pulmonary sepsis, or intrapulmonary infections. These studies follow directly from studies that are underway in the current funding period, and will provide important new information about the cellular and molecular events that contribute to acute lung injury in patients with sepsis.